Diagnostic potential of open lung biopsy in mechanically ventilated patients with diffuse pulmonary infiltrates of unclear aetiology.

Acute respiratory failure with bilateral pulmonary infiltrates is a clinical problem with a wide differential diagnosis. We evaluated whether open lung biopsy offered a diagnosis and therapeutic guidance in cases of unclear diagnosis after non-invasive tests. For this purpose, we reviewed 60 cases of open lung biopsy performed between 2002 and 2009 in patients with acute respiratory failure and bilateral infiltrates at the intensive care unit of Ghent University Hospital. Pathological diagnosis was classified as specific or non-specific and its contribution to therapy and decision-making was evaluated by a panel of three intensive care unit physicians. We found that a specific pathological diagnosis was present in 39 open lung biopsy patients (65%; 95% confidence interval 52 to 76%): idiopathic interstitial pneumonia in 24 patients, malignancy in four patients, pulmonary infectious disease in nine patients, and a combination of specific diagnoses in two patients. Open lung biopsy contributed to patient management in 53 cases (88%) as it led to the initiation, modification or discontinuation of therapeutic drugs in 36, and contributed to the decision to continue or withdraw ventilator support in 17. Complications of open lung biopsy were noted in 14 patients (23%). We conclude that open lung biopsy was a useful diagnostic intervention in of a selected group of patients with acute respiratory failure and bilateral infiltrates of unclear clinical diagnosis, as it offered a specific diagnosis in 65%.

Calcineurin and intracellular Ca2+-release channels: regulation or association?

The Ca(2+)- and calmodulin-dependent phosphatase calcineurin was reported to interact with the inositol 1,4,5-trisphosphate receptor (IP(3)R) and the ryanodine receptor (RyR) and to modulate their phosphorylation status and activity. However, controversial data on the molecular mechanisms involved and on the functional relevance of calcineurin for these channel-complexes have been described. Hence, we will focus on the functional importance of calcineurin for IP(3)R and RyR function and on the different mechanisms by which Ca(2+)-dependent dephosphorylation can affect the gating of those intracellular Ca(2+)-release channels. Since many studies made use of immunosuppressive drugs that are inhibiting calcineurin activity, we will also have to take the different side effects of these drugs into account for the proper interpretation of the effects of calcineurin on intracellular Ca(2+)-release channels. In addition, it became recently known that various other phosphatases and kinases can associate with these channels, thereby forming macromolecular complexes. The relevance of these enzymes for IP(3)R and RyR functioning will be reviewed since in some cases they could interfere with the effects ascribed to calcineurin. Finally, we will discuss the downstream effects of calcineurin on the regulation of the expression levels of intracellular Ca(2+)-release channels as well as the relation between IP(3)R- and RyR-mediated Ca(2+) release and calcineurin-dependent gene expression.